16, 17 [3&#39;, 1&#39;-(3&#39;-carboxy 2&#39; pyrazolino)] 20 pregnen-20-ones



United States Patent 1 6,17[3',1-(3-CARBOXY 2' PYRAZOLINO)] 20PREGNEN-20-ONES George P. Mueller, Park Ridge, 111., assignor to G. D.Searle & Co., Chicago, 11]., a corporation of Illinois No Drawing.Application February 1, 1955, Serial No. 485,609

Claims. (Cl. 260-2395) The present invention relates to a new group ofpentacyclic pyrazolinecarboxylic acids and, more particularly, to16,17-[3 ,1'-(3'-carboxy-2-pyrazolino) l-pregnen-ZO- ones containing anoxygen atom attached to the carbon atom in position 3 of ring A.

The compounds which constitute this invention can be represented by thestructural formula =0 NH CH3 COOH wherein one of the bonds linking thecarbon atom in position 5 to the carbon atoms in position 4 and 6 isunsaturated and wherein X: is a member of the class consisting of andradicals (lower alkyD-O o 0 In my copending application Serial No.349,984, filed April 20, 1953, of which the present application is acontinuation-in-part, there is described the preparation of the loweralkyl esters of the acids claimed herein from which they are derived byconventional deesterification procedures such as by heating with analkali metal hydroxide in an aqueous alcoholic solution.

The acids of this invention can also be used in the form of their loweralkali metal, lower alkaline earth metal, ammonium, and amine salts. Thecompounds of this invention have valuable pharmacological properties.They are effective cardiovascular drugs and cause a decrease inhypertensive blood pressure levels. They diifer from their lower alkylesters in their hormonal action. Specifically, they inhibit some of theundesirable side effects of cortisone without interfering with thetherapeutic actions of that hormone such as the anti-rheumatic effect.Cortisone is known to interfere with some of the defense mechanisms ofthe organism against the spread of infection and this is a seriouslimitation on its therapeutic applicability. On co-administration withcortisone, the acids of this invention and their salts prevent theatrophying efiect of cortisone on the lymph nodes and the sinus. Itappears that this effect is limited to the acids and their salts and islost on esterification since the lower alkyl esters do not produce thisanti-cortisone efiect.

The following examples describe in further detail certain of thecompounds which constitute this invention and methods for theirpreparation. However, the invention should not be construed as limitedthereby in spirit or in Patented Oct. 11, 1955 scope. It will be obviousto chemists skilled in the art that numerous modifications in methodsand materials may be adopted without departing from the scope of theinvention. In these examples, quantities of materials are indicated inparts by weight and temperatures in degrees centigrade.

EXAMPLE 1 16,17 [3,1 (3' car-boxy 2 pyratzolinofl A pregnen -3 ol 20 oneA mixture of 71 parts of 3-acetoxy-A pregnadien-ZO- one and 103 parts ofethyl diazoacetate is heated on an oil bath at 1l5120 C. for minutes.There is an evolution of gas and the crystal cake melts slowly. Oncooling a crystalline cake forms again. Successive recrystallizationsfrom benzene and from methanol yield the ethyl ester of3-acetoxy-16,17-[3,1-(3'-carlboxy-2'-pyrazolino)]-A -pregnen-20one,melting at about 217222 C. with decomposition.

A solution of 25 parts of potassium hydroxide in 50 parts of water and40 parts of methanol is refluxed with a solution of 5 parts of the ethylester of 3-acetoxy-16,17- [3 1'-( 3 '-carboxy-2-pyrazolino) ]-A-pregnen-2O-one in 800 parts of methanol for one hour under nitrogen.Then 400 parts of water are added and the mixture is chilled. Asuflicient amount of dilute hydrochloric acid is added to the filtrateto lower the pH to about 4. The resulting solution is partiallyconcentrated in vacuo. The precipitate is collected on a filter. The16,17-[3,l'-(3'-carboxy- 2-pyrazolino)l-A -pregnen-3-ol-20-one melts atabout 24l244 C. The compound has the structural formula C=0 NH CH3 l/ \NCOC'H EXAMPLE 2 3 acetoxy 16,17 [3,1, (3' carboxy 2 pyrazolin0)] Apregnen 20 one One part of 16,l7-[3',1'(3'-carboxy-2-pyrazolino)l- A-pregnen-3-ol-20-one is treated with 20 parts of acetic anhydride and 20parts of pyridine at room temperature for 20 hours and then poured onice and water. The mixture is extracted with ether and the ether extractis washed with dilute hydrochloric acid and water, dried over anhydroussodium sulfate and evaporated. Crystali=0 NH 0113 I ;N

C c to OH CHa--COO 3 EXAMPLE 3 3 butyroxy 16,17 [3',1.':(3 carboxy 2'pyrazolin)] A pregnen 20 one COOH EXAMPLE 4 16,17 r [3,1 (3' carboxy 2'pyraz0lin0)] A pregnene 3,17 dione A mixture of 31.2 parts of16-dehydroprogesterone and 25 parts of ethyl diazoacetate is heated at125 C. for an hour and the resulting gummy product is taken up in 1400parts of hot ether. The ether solution is evaporated to yield the ethylester of 16,17-[3',1-(3-carboxy-2-pyrazolino)]-A -pregnene-3,17-dione asa yellow oil.

Ten parts of this oily product are refluxed with 50 parts of potassiumhydroxide in 100 parts of water and 1700 parts of methanol for an hourunder nitrogen. Then 1000 parts of water are added and the mixture ischilled. A suflicient amount of dilute hydrochloric acid is added to thefiltrate to lower the pH to about 4 and the resulting solution ispartially concentrated under vacuum. A precipitate is formed which iscollected on a filter. There is thus obtained the16,17-[3',1'-(3-carboxy-2-pyrazolino)]-A -pregnene-3,17-dione which hasthe structural formula I COOH The infrared absorption spectrum showsmaxima at 5.80, 6.02, and 6.40 microns.

What is claimed is:

1. A member of the class consisting of the compounds of the structuralformulas C=O NH OH: I

| COOH and C=O NH wherein X is a member of the class consisting ofhydrogen and (lower alkyl)-CO radicals.

2. A compound of the structural formula 3. A compound ofthe structuralformula CH i e I COOH 4. A compound of the structural formula CHa-C O 0No references cited.

1. A MEMBER OF THE CLASS CONSISTING OF THE COMPOUNDS OF THE STRUCTURALFORMULAS